ORGANIC LETTERS
Catalytic Enantioselective Total Syntheses of Bakkenolides I, J, and S: Application of a Carbene-Catalyzed Desymmetrization
2010 Vol. 12, No. 12 2830-2833
Eric M. Phillips, John M. Roberts, and Karl A. Scheidt* Department of Chemistry, Center for Molecular InnoVation and Drug DiscoVery, Chemistry of Life Processes Institute, SilVerman Hall, Northwestern UniVersity, EVanston, Illinois 60208
[email protected] Received April 23, 2010
ABSTRACT
A general strategy for the catalytic asymmetric syntheses of the bakkenolides is reported. The key bond-forming step involves an N-heterocyclic carbene catalyzed desymmetrization of a 1,3-diketone to form three new bonds in one step with excellent enantio- and diastereoselectivity. This intramolecular reaction allows direct access to the hydrindane core of the bakkenolide family and enables a facile synthesis of these natural products.
The bakkanes are a large class of sesquiterpene natural products containing a characteristic cis-fused 6,5-bicyclic core.1 The first isolation of a bakkane was reported in 1968, and ensuing investigations have identified over 50 members in this family.2 The bakkenolides are biogenetically related to the eremophilanes, and the conversion of the initial decalin core to the 6,5 system is proposed to involve an intriguing oxidative ring contraction.3 These natural products possess a wide spectrum of biological activity including antifeedant effects, platelet aggregation inhibition, and potent inhibitory activity against a variety of tumor cell lines.4 The five contiguous stereocenters around the hydrindane core, including two quaternary carbons and the spiro γ-butyrolactone, (1) (a) Silva, L. F. Synthesis 2001, 671. (b) Brocksom, T. J.; Brocksom, U.; Constantino, M. G. Quim. NoVa 2008, 31, 937. (2) (a) Abe, N.; Onoda, R.; Shirahat, K.; Kato, T.; Woods, M. C.; Kitahara, Y. Tetrahedron Lett. 1968, 369–373. (b) Wu, T. S.; Kao, M. S.; Wu, P. L.; Lin, F. W.; Shi, L. S.; Liou, M. J.; Li, C. Y. Chem. Pharm. Bull. 1999, 47, 375–382. (3) (a) Reference 2. (b) Marshall, J. A.; Cohen, G. M. J. Am. Chem. Soc. 1971, 36, 877–882. 10.1021/ol100938j 2010 American Chemical Society Published on Web 05/14/2010
present an inspiring challenge to the application of modern asymmetric methodology. With their compact topology combined with useful biological activity, this natural product family has elicited considerable attention since the total synthesis of (()bakkenolide A by Evans.5 The majority of syntheses of the bakkenolides are racemic and have relied on efficient DielssAlder or [2 + 2] cycloadditions to build the hydrindane core.6 The asymmetric synthetic approaches reported to date rely primarily on chiral pool technology. Recent asymmetric work by Silva begins with the WielandsMiescher ketone and is highlighted by a novel ring contraction.7 Two examples reported previously start with carvone8 or employ (s)-N-methylephedrine reduction technology.6b The dearth of catalytic enantioselective approaches to these molecules (4) (a) Jamieson, G. R.; Reid, E. H.; Turner, B. P.; Jamieson, A. T. Phytochemistry 1976, 15, 1713–1715. (b) Kano, K.; Hayashi, K.; Mitsuhashi, H. Chem. Pharm. Bull. 1982, 30, 1198–1203. (5) Evans, D. A.; Sims, C. L.; Andrews, G. C. J. Am. Chem. Soc. 1977, 99, 5453–5461.
to date is an opportunity to challenge the boundaries of asymmetric catalysis in the context of synthesis and provide new means to efficiently prepare optically active bakkanes. The field of N-heterocyclic carbene catalysis has undergone significant development recently,9 and its application in complex molecule synthesis is an emerging area.10 Carbene catalysis provides efficient access to a variety of nucleophilic species (e.g., acyl anion, homoenolate, enolate) with high levels of stereoselectivity and is particularly attractive for integration into synthetic strategies as a key bond-forming tactic. We report herein the efficient, enantioselective total syntheses of (s)-bakkenolides I, J, and S utilizing a cascade homonenolate protonation/intramolecular aldol/acylation sequence catalyzed by an N-heterocyclic carbene (NHC) (Scheme 1).
Scheme 2. NHC-Catalyzed Desymmetrization
Scheme 1. Synthetic Approach
The key structural element in this family of natural products is the fused 6,5-bicyclic ring system that contains an angular methyl group flanked by tertiary and spiro quaternary carbon atoms. We envisaged the core of these molecules being synthesized using our recently reported NHC-catalyzed desymmetrization of 1,3-diketones (Scheme 2).11 This strategy would allow us to control the formation of the key quaternary stereogenic center present in all the (6) (a) Greene, A. E.; Depre´s, J. P.; Coelho, F.; Brocksom, T. J. J. Org. Chem. 1985, 50, 3943–3945. (b) Greene, A. E.; Coelho, F.; Depre´s, J. P.; Brocksom, T. J. Tetrahedron Lett. 1988, 29, 5661–5662. (c) Back, T. G.; Nava-Salgado, V. O.; Payne, J. E. J. Org. Chem. 2001, 66, 4361–4368. (d) Hamelin, O.; Depre´s, J.-P.; Greene, A. E.; Tinant, B.; Declercq, J.-P. J. Am. Chem. Soc. 1996, 118, 9992–9993. (e) Hamelin, O.; Depre´s, J.-P.; Heidenhain, S.; Greene, A. E. Nat. Prod. Lett. 1997, 10, 99–103. (f) Hamelin, O.; Wang, Y.; Depre´s, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000, 39, 4314–4316. (g) Brocksom, T. J.; Coelho, F.; Depre´s, J. P.; Greene, A. E.; de Lima, M. E. F.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.; Wang, Y. Y. J. Am. Chem. Soc. 2002, 124, 15313–15325. (7) Carneiro, V. M. T.; Ferraz, H. M. C.; Vieira, T. O.; Ishikawa, E. E.; Silva, L. F. J. Org. Chem. 2010, 75, 2877–2882. (8) (a) Jiang, C. H.; Bhattacharyya, A.; Sha, C. K. Org. Lett. 2007, 9, 3241–3243. (b) Hartmann, B.; Kanazawa, A. M.; Depre´s, J.-P.; Greene, A. E. Tetrahedron Lett. 1993, 34, 3875–3876. (9) (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534–541. (b) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130–5135. (c) Marion, N.; Diez-Gonzalez, S.; Nolan, I. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000. (d) Phillips, E. M.; Chan, A.; Scheidt, K. A. Aldrichim. Acta 2009, 42, 55–66. Org. Lett., Vol. 12, No. 12, 2010
bakkenolides starting from readily available material and produce appropriate functional groups for further elaboration. The synthesis of the required symmetric 1,3-diketone began with the palladium-catalyzed addition of 2-methy-1,3cyclohexadione (1) to butadiene monoepoxide. A subsequent TEMPO-catalyzed oxidation of the allylic alcohol furnished the R,β-unsaturated aldehyde (2, 59% for two steps). In the key bonding-forming event, the achiral aldehyde (2) underwent a tandem homoenolate protonation, intramolecular aldol addition, and acylation in the presence of 5 mol % A and generated the desired β-lactone 3 in 69% yield. An interesting facet of this reaction is the isolation of the β-lactone product. In our 2007 work with this desymmetrizing aldol reaction,11 substrates with aromatic ketones readily decarboxylate under the reaction conditions to yield substituted cyclopentene rings.12 This highly selective desymmetrization reaction can be performed on a 5 g scale and affords the tricyclic product with excellent levels of diastero- and enantioselectivity (>20:1 dr, 98% ee). The concentration was increased, and the reaction temperature was lowered from 40 to 35 °C to accommodate larger reaction scales, which slightly improved both the yield and enantioselectivity. With β-lactone 3 in hand, the installation of an oxygen atom directly to the C-9 position was required. As a prelude (10) For total syntheses employing carbene catalysis, see: (a) Trost, B. M.; Shuey, C. D.; Dininno, F. J. Am. Chem. Soc. 1979, 101, 1284– 1285. (b) Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509–8514. (c) Takikawa, H.; Suzuki, K. Org. Lett. 2007, 9, 2713–2716. (d) Koyama, Y.; Yamaguchi, R.; Suzuki, K. Angew. Chem., Int. Ed. 2008, 47, 1084–1087. (e) Nicolaou, K. C.; Nold, A. L.; Li, H. M. Angew. Chem., Int. Ed. 2009, 48, 5860–5863. (11) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098–10099. (12) For the first report of this decarboxylation in carbene-catalyzed reactions to yield cyclopentenes (although prurportedly through a homoenolate and not enolate pathway), see: Nair, V.; Vellalath, S.; Poonoth, S.; Suresh, E. J. Am. Chem. Soc. 2006, 128, 8736–8737. 2831
to this oxidation, the decarboxylation of 3 in the presence of silica gel13 followed by protection of the ketone using Noyori’s protocol allowed for the successful installation of the ketal, whereas typical Dean-Stark conditions resulted in poor yields.14 A hydroboration of the alkene occurred from the convex face of 4, resulting in formation of the secondary alcohol in a high yield (75%) with >20:1 regio- and diastereoselection. The reformation of the ketone was facilitated with p-TsOH in acetone followed by protection of the secondary alcohol with TBSCl and imidazole (98% yield for two steps). A subsequent Wittig olefination of the sterically hindered ketone 6 successfully installed the exomethylene subunit of 7 (81%) (Scheme 3).
Scheme 3. Construction of Olefin 7
fortuitous since alkene 8 could be independently converted to 10 and 9 in a 6:1 ratio in the presence of Pd/C and hydrogen at elevated pressure. With these results in hand, we explored conditions to promote the isomerization cleanly since this reaction followed by the stereoselective reduction would be the superior route (7 to 8 to 10). Exposure to mild reduction conditions such as PdBaSO4 in the presence of H2 improved the ratio, but the results were not satisfactory. Attempts at isomerization with elevated reaction temperatures also failed to improve the efficiency of the reaction. Finally, we found that 1 mol % of Crabtree’s catalyst ([(cod)(pyr)(PCy3)Ir]PF6)16 successfully provided internal alkene 8 in 99% yield from 7, which allowed us to proceed with the Pd/C reduction to afford 10 (69%). Minimized structures of 8, 9, and 10 (MM2 Spartan) suggest that there are subtle torsional effects that control the facial selectivity of this reduction. The undesired isomer 9 is higher in energy than 10 due to the axial methyl group, and this difference may direct a more late-type transition state for this hydrogenation. The conversion of silyl ether 10 to ketone 11 was accomplished with TBAF followed by Dess-Martin periodinane (98%, two steps). An acylation of the kinetic enolate with Mander’s reagent17 followed by trans-esterification with propargyl alcohol yielded β-keto propargyl ester 12 as a 9:1 mixture of diastereomers.18 At this juncture, the formation of the key butyrolactone using a Conia-ene reaction was investigated (Table 2).19
Table 2. Investigation of Lactone Formation
The reduction of the newly formed alkene within 7 to generate the necessary vicinal methyl substituents was not straightforward. A survey of numerous reduction conditions yielded at best a 1:1 ratio of the desired diastereomer 10 and 9. The use of Et3SiH in combination with Pd/C and H2 led to an increase in 10 but also promoted isomerization to the endocyclic olefin (8) (Table 1).15 This observation proved
entry
conditions
yielda (%)
1
5 mol % (PPh3)AuCl, AgOTf, CH2Cl2 5 mol % [(PPh3)Au)3O]BF4, HOTf, DCE Mn(OAc)3·H2O, EtOH
